Chronic relapsing and remitting inflammation of the gastrointestinal tract are hallmarks of ulcerative colitis and Crohn's disease, conditions termed inflammatory bowel diseases (“IBD”). The peak age of onset of this disease is between the first and fourth decades of life, with a prevalence of 100-200 per 100,000 in Europe and North America. Inflammatory bowel disease accounts for significant morbidity and decreased quality of life, and is responsible for nearly US$2.0 billion in annual medical costs in the United States. Although there has been progress in defining the pathogenesis of these diseases, their cause remains obscure. The current most comprehensive hypothesis is that IBD is a heterogeneous group of diseases that have a final manifestation, which is mucosal inflammation, and that several genetic and environmental factors are implicated in the pathogenesis of the disease.
Because of the name, IBD is often confused with irritable bowel syndrome (“IBS”), a troublesome but much less serious condition. Irritable bowel syndrome is a gastrointestinal disorder characterized by altered bowel habits and abdominal pain in the absence of detectable structural abnormalities, such as inflammation or ulceration. Irritable bowel syndrome is not an inflammatory disease and it is not characterized by ulceration of the bowel. No clear diagnostic markers exist and no pathognomonic abnormalities have been identified for IBS, so all definitions of the disease are based on the clinical presentation. Until recently, many physicians did not consider IBS to be a disease at all; they viewed it as nothing more than a somatic manifestation of psychological stress. Typical chemotherapies for IBS include stool bulking agents, antispasmodics, and antidiarrheal agents.
In contrast, Crohn's disease is an inflammatory disease characterized by transmural, patchy, granulomatous inflammation of any part of the gastrointestinal tract, although it is common in the ileocecal area. Symptoms of Crohn's disease include abdominal pain, diarrhea, gastrointestinal bleeding, malabsorption, and weight loss. Although the etiology is unknown, research suggests it involves a complex interplay of environmental, genetic, microbial, immune, and nonimmune factors. Biopsies obtained from the bowel in subjects with Crohn's disease reveal inflammatory cells suggesting that the bowel is either reacting immunologically to a stimulus or the endogenous immune system of the gastrointestinal track is off balance.
Treatment of Crohn's disease usually includes administration of anti-inflammatory drugs, including compounds designed to reduce the inflammatory response, such as corticosteroids, cyclosporine, and azathioprine, which often lead to serious side effects. Major advances in the understanding of the pathogenesis of IBD have led to the development of novel immunotherapies. Such treatments include the administration of chimeric monoclonal antibodies specific for molecules expressed by the T-cells population or antibodies specific for cytokines known to be central to the pathogenesis of mucosal inflammation (anti-tumor necrosis factor, TNF). Although this specific immunotherapy has helped those with Crohn's disease, still about 20% do not respond to this treatment and many cannot continue this therapy due to untoward side effects. Additionally, treatment with the monoclonal antibody infliximab (sold as REMICADE®, a registered trademark of Centocor, Inc. of Malvern, Pa.) is expensive with each infusion costing in excess of US$3,000.
Ulcerative colitis is a form of colitis, an inflammatory disease of the intestine, usually the colon, that includes characteristic ulcers. Symptoms of active disease usually include diarrhea mixed with blood, usually accompanied with varying degrees of abdominal pain, from mild discomfort to severely painful cramps. Although ulcerative colitis has no known cause, there is a presumed genetic component to susceptibility. The disease may be triggered in a susceptible person by environmental factors. Although dietary modification may reduce the discomfort of a person with the disease, ulcerative colitis is not thought to be caused by dietary factors. As with Crohn's disease, treatment includes administration of anti-inflammatory drugs, immunosuppression, and biological therapy targeting specific components of the immune response.
When anti-inflammatory therapies fail, colectomy is occasionally necessary, which is considered to be curative for ulcerative colitis. Surgery is generally reserved for complications of Crohn's disease or when disease that resists treatment with drugs is confined to one location that can be removed. Surgery is also used to manage complications of Crohn's disease, such as fistulae and small bowel obstructions, and for resection and anastomosis (e.g., ileocolonic resection). Surgery rarely cures Crohn's disease, and recurrence often reappears in previously unaffected areas of the intestine.
Accordingly, a continuing need exists for effective pharmacological treatments of inflammatory bowel disease, such as Crohn's disease and ulcerative colitis.